Polycystic Ovary Syndrome (PCOS) is a complex phenotype that is defined by elevated testosterone levels and amenorrhea/oligomenorrhea. It occurs in ~7% of reproductive age women and is also strongly associated with obesity, insulin resistance, and an increased risk of developing Type 2 Diabetes (T2D). While PCOS has a strong familial component and has been shown to be highly heritable (h2=0.8), traditional genetic studies conducted by our laboratory and others have identified only a limited number of reproducible PCOS susceptibility genetic loci. It is clear from current genetic studies of PCOS and other complex genetic phenotypes that common genetic variation does not explain the bulk of the observed heritability. One possible explanation for this observed deficit is that the observed heritability in complex phenotypes is due to epigenetic rather than genomic variation. Epigenetic changes are heritable changes in gene expression or cellular phenotype that occur in the absence of changes to the DNA sequence. Variation in DNA methylation patterns is one major form of epigenetic variation and can be captured on a genomic level using methylation specific DNA arrays that test >450,000 DNA methylation sites. We hypothesize that: 1) a significant component of the heritability of PCOS is due to epigenetic changes including variation in niethylation pattern, 2) these changes in methylation patterns correlate with changes in expression patterns, and 3) these changes in methylation are due to either specific changes in the DNA or environmental factors including the in utero environment. We propose to test these hypotheses by assessing the differential DNA methylation status in target tissues (muscle, visceral fat, subcutaneous fat, and liver) of obese women with and without PCOS, the impact of differential methylation on gene expression, and whether the differential methylation status is due to genomic or epigenetic event. PCOS is common syndrome which severely impacts the health of affected women and their first degree relatives and contributes greater than $4 billion annually to our health care costs. The proposed studies will increase our understanding to the underlying pathways that are affected in PCOS and with the potential of improved treatment for this pervasive syndrome. RELEVANCE (See instructions); PCOS is a common disorder defined by elvated male sex hormones and irregular menses and is strongly associated with obesity and diabetes. Current genetic approaches have failed to identify the bulk of the hertitable factors contributing to PCOS susceptibility. We propose to asses the role of epigenetic variation, heritable changes in gene expression that occur in the absence of DNA changes, in the cause of PCOS